Immune-related endocrinopathy in cancer patients receiving immune checkpoint inhibitor therapy in the nationwide prospective DIRECT cohort.

12132 Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, extending patient survival. However, side effects such as endocrinopathies are common and have severe, sometimes irreversible outcomes if not managed promptly. Predictive factors for endocrinopathies are poorly understood. We examined whether demographic and clinical characteristics are linked with the development of ICI-induced endocrinopathies. Methods: The DiRECT Cohort (URCC21038, NCT05364086) is an ongoing observational trial of cancer patients scheduled to receive anti-PD-(L)1 ICI therapy and enrolled through the URCC NCORP Research Base nationwide network. This analysis was based on 1,525 patients with toxicity data assessed 12/31/2024. Endocrinopathies were graded using the Common Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0. Toxicity data was collected after each infusion of ICI. Demographics (age, sex, BMI, race) and clinical factors (cancer type, cancer stage, treatment agent, autoimmune disease, and significant comorbidities) were collected at baseline. We tested bivariate associations with chi-square tests and multivariable associations with logistic regression; statistical significance was set at a p-value of 0.05. Results: Of the 1.525 participants, 533 (35%) had lung cancer, 263 (17.3%) had breast cancer, 812 (53.3%) were aged ≥ 65, 1142 (75.4%) White, 828 (54.4%) women, 1009 (66.3%) had BMI < 30, 802 (52.7%) had at least one comorbidity, and 128 (8.4%) had an autoimmune disease, 831 (55.2%) had stage IV cancer, and 930 (61.1%) were on pembrolizumab. 252 (16.5%) developed endocrinopathies of any grade: Hyperthyroidism, 61 (24.2%); Hypothyroidism, 156 (61.9%); Thyrotoxicosis, 7 (2.75%); and Adrenal insufficiency, 11 (4.37%). The most common of these were hypo/hyperthyroidism, of which 9% were grade ≥2. In bivariate analyses, grade >2 endocrinopathies were associated with younger age (11% age < 65 vs. 7% age ≥65, p = 0.012), female sex (10% in women vs. 4% in men, p = 0.001), and obesity (12% of those with BMI >30 vs 7% with BMI < 30, p = 0.001). We found no significant associations with other factors evaluated. In multivariable logistic regression analyses, younger age, female sex, and obesity were significant predictors, with higher odds of endocrinopathy for those of age < 65 (OR: 1.58, 95% CI: 1.35-1.85), female sex (OR: 1.75, 95% CI: 1.48-2.08), with BMI ≥30 (OR: 1.97, 95% CI: 1.68-2.31). Conclusions: In this nationwide observational trial, younger age, female sex, and obesity were associated with a higher likelihood of developing grade ≥2 ICI-induced endocrinopathies. Future work will focus on identifying biomarkers predictive of endocrinopathy and developing predictive models for risk stratification.